Various central nervous system disorders such as anxiety, depression, motor disorders, etc., are believed to involve a disturbance of the neurotransmitter 5-hydroxytryptamine (5-HT) or serotonin. Serotonin is localized in the central and peripheral nervous systems and is known to affect many types of conditions including psychiatric disorders, motor activity, feeding behavior, sexual activity, and neuroendocrine regulation among others. The effects of serotonin are regulated by the various 5-HT receptor subtypes. Known 5-HT receptors include the 5-HT1 family (e.g. 5-HT1 A), the 5-HT2 family (e.g. 5-HT2A), 5-HT3,5-HT4,5-HT5,5-HT6 and 5-HT7 subtypes.
The recently identified human 5-hydroxytryptamine-6 (5-HT6) receptor subtype has been cloned, and the extensive distribution of its mRNA has been reported. Highest levels of 5-HT6 receptor mRNA have been observed in the olfactory tubercle, the striatum, nucleus accumbens, dentate gyrus and CA1, CA2 and CA3 regions of the hippocampus. Lower levels of 5-HT6 receptor mRNA are seen in the granular layer of the cerebellum, several diencephalic nuclei, amygdala and in the cortex.
Northern blots have revealed that 5-HT6 receptor mRNA appears to be exclusively present in the brain, with little evidence for its presence in peripheral tissues. The high affinity of a number of antipsychotic agents for the 5-HT6 receptor, in addition to its mRNA localization in striatum, olfactory tubercle and nucleus accumbens suggests that some of the clinical actions of these compounds may be mediated through this receptor. Therefore, 5-HT6 receptor ligands are believed to be of potential use in the treatment of certain CNS disorders such as anxiety, depression, epilepsy, obsessive compulsive disorder, attention deficit disorder, migraine, cognitive memory enhancement (e.g. for the treatment of Alzheimer""s disease), sleep disorders, feeding disorders (e.g. anorexia or bulimia), neurodegeherative disorders (e.g. stroke or head trauma), panic attacks, withdrawal from drug abuse (e.g. cocaine, ethanol, nicotine or benzodiazepines), schizophrenia, or the like; or in the treatment of certain gastrointestinal disorders such as irritable bowel syndrome.
Therefore, it is an object of this invention to provide compounds which are useful as therapeutic agents in the treatment of a variety of central nervous system disorders related to or affected by the 5-HT6 receptor.
It is another object of this invention to provide therapeutic methods and pharmaceutical compositions useful for the treatment of central nervous system disorders related to or affected by the 5-HT6 receptor.
It is a feature of this invention that the compounds provided may also be used to further study and elucidate the 5-HT6 receptor.
These and other objects and features of the invention will become more apparent by the detailed description set forth hereinbelow.
The present invention provides a pyrrolylalkylidene-hydrazinecarboximidamide derivative of formula I 
wherein
Q is SO2, CO, CH2, CO2, CONH or CSNH;
R1, R2, R3 and R4 are each independently H or a C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C10cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group each optionally substituted or R1 and R2 may be taken together with the atoms to which they are attached to form a 5-, 6- or 7-membered ring;
R5 is H or R4 and R5 may be taken together with the atoms to which they are attached to form a 5-, 6- or 7-membered ring;
R6 is a C1-C6alkyl, aryl or heteroaryl group each optionally substituted;
R7 is H, halogen, NO2, CN, OR8, NR9R10, OCO2R11, OCONR12R13, CO2R14, COR15, CONR16R17 or SO2NR18R19 or a C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group each optionally substituted;
R8, R11, R14 and R15 are each independently H or a C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group each optionally substituted; and
R9, R10, R12, R13, R16, R17, R18 and R19 are each independently H or an optionally substituted C1-C6alkyl group or R9 and R10 may be taken together with the atom to which they are attached to form a 5-, 6- or 7-membered ring optionally containing another heteroatom selected from O, N or S; or
the stereoisomers thereof or the pharmaceutically acceptable salts thereof.
The present invention also provides methods and compositions useful for the therapeutic treatment of central nervous system disorders related to or affected by the 5-HT6 receptor.
The 5-hydroxytryptamine-6 (5-HT6) receptor is one of the most recent receptors to be identified by molecular cloning. Its ability to bind a wide range of therapeutic compounds used in psychiatry, coupled with its intriguing distribution in the brain has stimulated significant interest in new compounds which are capable of interacting with or affecting said receptor. Significant efforts are being made to understand the possible role of the 5-HT6 receptor in psychiatry, cognitive dysfunction, motor function and control, memory, mood and the like. To that end, compounds which demonstrate a binding affinity for the 5-HT6 receptor are earnestly sought both as an aid in the study of the 5-HT6 receptor and as potential therapeutic agents in the treatment of central nervous system disorders, for example see C. Reavill and D.C. Rogers, Current Opinion in Investigational Drugs, 2001, 2(1):104-109, Pharma Press Ltd.
Surprisingly, it has now been found that pyrrolylalkylidene-hydrazine-carboximidamide derivatives of formula I demonstrate 5-HT6 affinity. Advantageously, said hydrazine derivatives may be used as effective therapeutic agents for the treatment of central nervous system (CNS) disorders associated with or affected by the 5-HT6 receptor. Accordingly, the present invention provides pyrrolylalkylidene-hydrazinecarboximidamide derivatives of formula I 
wherein
Q is SO2, CO, CH2, CO2, CONH or CSNH;
R1, R2, R3 and R4 are each independently H or a C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C10cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group each optionally substituted or R1 and R2 may be taken together with the atoms to which they are attached to form a 5-, 6- or 7-membered ring;
R5 is H or R4 and R5 may be taken together with the atoms to which they are attached to form a 5-, 6- or 7-membered ring;
R6 is a C1-C6alkyl, aryl or heteroaryl group each optionally substituted;
R7 is H, halogen, NO2, CN, OR8, NR9R10, OCO2R11, OCONR12R13, CO2R14, COR15, CONR16R17 or SO2NR18R19 or a C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group each optionally substituted;
R8, R11, R14 and R15 are each independently H or a C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group each optionally substituted; and
R9, R10, R12, R13, R16, R17, R18 and R19 are each independently H or an optionally substituted C1-C6alkyl group or R9 and R10 may be taken together with the atom to which they are attached to form a 5-, 6- or 7-membered ring optionally containing another heteroatom selected from O, N or S; or
the stereoisomers thereof or the pharmaceutically acceptable salts thereof.
As used in the specification and claims, the term halogen designates Br, Cl, I or F and the term cycloheteroalkyl designates a five- to seven-membered cycloalkyl ring system containing 1 or 2 heteroatoms, which may be the same or different, selected from N, O or S and optionally containing one double bond. Exemplary of the cycloheteroalkyl ring systems included in the term as designated herein are the following rings wherein X is NR, O or S; and R is H or an optional substituent as described hereinbelow: 
Similarly, as used in the specification and claims, the term heteroaryl designates a C5-C10 aromatic ring system containing 1, 2 or 3 heteroatoms, which may be the same or different, selected from N, O or S. Such heteroaryl ring systems include pyrrolyl, azolyl, oxazolyl, thiazolyl, imidazolyl, furyl, thienyl, quinolinyl, isoquinolinyl, indolinyl, benzothienyl, benzofuranyl, benzisoxazolyl or the like. The term aryl designates a carbocyclic aromatic ring system such as phenyl, naphthyl, anthracenyl or the like. The term haloalkyl as used herein designates a CnH2n+1 group having from one to 2n+1 halogen atoms which may be the same or different and the term haloalkoxy as used herein designates an OCnH2n+1 group having from one to 2n+1 halogen atoms which may be the same or different.
In the specification and claims, when the terms C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C7cycloalkyl, cycloheteroalkyl, aryl or heteroaryl as designated as being optionally substituted, the substituent groups which are optionally present may be one or more of those customarily employed in the development of pharmaceutical compounds or the modification of such compounds to influence their structure/activity, persistence, absorption, stability or other beneficial property. Specific examples of such substituents include halogen atoms, nitro, cyano, thiocyanato, cyanato, hydroxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, amino, alkylamino, dialkylamino, formyl, alkoxycarbonyl, carboxyl, alkanoyl, alkylthio, alkylsuphinyl, alkylsulphonyl, carbamoyl, alkylamido, phenyl, phenoxy, benzyl, benzyloxy, heterocyclyl or cycloalkyl groups, preferably halogen atoms or lower alkyl groups. Typically, 0-3 substituents may be present. When any of the foregoing substituents represents or contains an alkyl substituent group, this may be linear or branched and may contain up to 12, preferably up to 6, more preferably up to 4 carbon atoms.
Pharmaceutically acceptable salts may be any acid addition salt formed by a compound of formula I and a pharmaceutically acceptable acid such as phosphoric, sulfuric, hydrochloric, hydrobromic, citric, maleic, malonic, mandelic, succinic, fumaric, acetic, lactic, nitric, sulfonic, p-toluene sulfonic, methane sulfonic acid or the like.
Compounds of the invention include esters, carbamates or other conventional prodrug forms, which in general, are functional derivatives of the compounds of the invention and which are readily converted to the inventive active moiety in vivo. Correspondingly, the method of the invention embraces the treatment of the various conditions described hereinabove with a compound of formula I or with a compound which is not specifically disclosed but which, upon administration, converts to a compound of formula I in vivo. Also included are metabolites of the compounds of the present invention defined as active species produced upon introduction of these compounds into a biological system.
Compounds of the invention may exist as one or more stereoisomers. The various stereoisomers include enantiomers, diastereomers, atropisomers and geometric isomers. One skilled in the art will appreciate that one stereoisomer may be more active or may exhibit beneficial effects when enriched relative to the other stereoisomer(s) or when separated from the other stereoisomer(s). Additionally, the skilled artisan knows how to separate, enrich or selectively prepare said stereoisomers. Accordingly, the present invention comprises compounds of Formula I, the stereoisomers thereof and the pharmaceutically acceptable salts thereof. The compounds of the invention may be present as a mixture of stereoisomers, individual stereoisomers, or as an optically active or enantiomerically pure form.
Preferred compounds of the invention are those compounds of formula I wherein Q is SO2. Also preferred are those compounds wherein R4 is H or CH3. Another group of preferred formula I compounds are those compounds wherein R6 is an optionally substituted phenyl or heteroaryl group.
More preferred compounds of the invention are those compounds of formula I wherein Q is SO2 and R6 is an optionally substituted phenyl or heteroaryl group. Another group of more preferred compounds of the invention are those formula I compounds wherein Q is SO2; R4 is H or CH3; R5 is H; and R6 is an optionally substituted phenyl or heteroaryl group. Further more preferred compounds of formula I are those compounds wherein Q is SO2; R1, R2, R3, R5 and R7 are H; R4 is H or CH3; and R6 is an optionally substituted phenyl or heteroaryl group.
Among the preferred compounds of the invention are:
2-{(E)-1-[1-(phenylsulfonyl)-1H-pyrrol-3-yl]ethylidene}hydrazinecarboximidamide;
2-{(E)-1-[1-(4-methylphenylsulfonyl)-1H-pyrrol-3-yl]ethylidene}hydrazine-carboximidamide;
2-{(E)-1-[1-(2,4-dimethyl-1-(phenylsulfonyl)-1H-pyrrol-3-yl]ethylidene}hydrazine-carboximidamide;
2-{(E)-1-[1-(naphthylsulfonyl)-1H-pyrrol-3-yl]ethylidene}-1-hydrazine-carboximidamide;
2-{(E)-1-{1-(5-chloro-3-methyl-1-benzothiophen-2-yl)sulfonyl]-1H-pyrrol-3-yl}ethylidene)-1-hydrazinecarboximidamide;
2-((E)-1-{1-[(4-aminophenyl)sulfonyl]-1H-pyrrol-3-yl}ethylidene)-1-hydrazine-carboximidamide;
2-((E)-1-{1-[(2-amino-4-methyl-1,3-thiazol-5-yl)sulfonyl]-1H-pyrrol-3-yl}ethylidene)-1-hydrazinecarboximidamide;
2-[1-[(phenylsulfonyl)-1,5,6,7-tetrahydro-4H-indol-4-ylidene]-1-hydrazinecarboximidamide;
2-[1-(4-biphenylsulfonyl)-1,5,6,7-tetrahydro-4H-indol-4-ylidene]-1-hydrazinecarboximidamide;
2-[1-(4-bromophenylsulfonyl)-1,5,6,7-tetrahydro-4H-indol-4-ylidene]-1-hydrazinecarboximidamide;
2-[1-(5-chloro-2-methoxyphenylsulfonyl)-1,5,6,7-tetrahydro-4H-indol-4-ylidene]-1-hydrazinecarboximidamide;
the stereoisomers thereof; or the pharmaceutically acceptable salts thereof.
Compounds of the invention may be prepared by using conventional synthetic methods and, if required, standard separation and isolation techniques. For example, compounds of formula I wherein Q is SO2 and R5 is H (Ia) may be prepared by reacting a 3-acylpyrrole compound of formula III with a sulfonyl chloride, R6SO2Cl, in the presence of a base, such as NaH, to give the corresponding 1-sulfonyl-3-acylpyrrole of formula II and condensing said pyrrole with an aminoguanidine of formula IV to give the desired formula Ia product. The reaction is shown in flow diagram I. 
Compounds of formula I wherein Q is SO2 and R4 and R5 are taken together with the atoms to which they are attached to form a 5-, 6- or 7-membered ring (Ib) may be prepared by reacting the appropriate pyrrole derivative of formula V with a sulfonyl chloride, R6SO2Cl, to form the corresponding N-sulfonyl compound of formula VI and condensing said formula VI compound with an aminoguanidine of formula IV to give the desired product of Formula Ib. The reaction is shown in flow diagram II wherein n is an integer of 1, 2 or 3. 
Similarly, compounds of formula I wherein Q is CO, CH2, CO2, CONRR or CSNRR may be prepared using the above procedures illustrated in flow diagram I and II and employing the appropriately substituted acid chloride, alkylhalide, chloroformate, isocyanate or isothiocyanate, respectively, in place of R6SO2Cl.
Advantageously, the present invention provides a process for the preparation of a compound of formula I which comprises reacting a compound of formula IIa with an aminoguanidine of formula IV in the presence of an acid, optionally in the presence of a solvent. The process of the invention is shown in flow diagram III. 
Acids suitable for use in the process of the invention include acids such as HCl, HBr, H2SO4, HNO2 or the like, preferably HCl. Solvents suitable for use in the process of invention include protic solvents such as lower alkyl alcohols, i.e., methanol, ethanol, isopropanol, propanol or the like, preferably isopropanol.
Advantageously, the inventive compound of formula I may-be utilized in the treatment of central nervous system disorders relating to or affected by the 5-HT6 receptor such as motor, mood, psychiatric, cognitive, neurodegenerative, or the like disorders, for example, Alzheimer""s disease, Parkinson""s disease, attention deficit disorder, anxiety, epilepsy, depression, obsessive compulsive disorder, migraine, sleep disorders, neurodegenerative disorders (such as head trauma or stroke), feeding disorders (such as anorexia or bulimia), schizophrenia, memory loss, disorders associated with withdrawal from drug or nicotine abuse, or the like or certain gastrointestinal disorders such as irritable bowel syndrome. Accordingly, the present invention provides a method for the treatment of a disorder of the central nervous system (CNS) related to or affected by the 5-HT6 receptor in a patient in need thereof which comprises providing said patient a therapeutically effective amount of a compound of formula I as described hereinabove. The compounds may be provided by oral or parenteral administration or in any common manner known to be an effective administration of a therapeutic agent to a patient in need thereof.
The therapeutically effective amount provided in the treatment of a specific CNS disorder may vary according to the specific condition(s) being treated, the size, age and response pattern of the patient, the severity of the disorder, the judgment of the attending physician and the like. In general, effective amounts for daily oral administration may be about 0.01 to 1,000 mg/kg, preferably about 0.5 to 500 mg/kg and effective amounts for parenteral administration may be about 0.1 to 100 mg/kg, preferably about 0.5 to 50 mg/kg.
In actual practice, the compounds of the invention are provided by administering the compound or a precursor thereof in a solid or liquid form, either neat or in combination with one or more conventional pharmaceutical carriers or excipients. Accordingly, the present invention provides a pharmaceutical composition which comprises a pharmaceutically acceptable carrier and an effective amount of a compound of formula I as described hereinabove.
Solid carriers suitable for use in the composition of the invention include one or more substances which may also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aides, binders, tablet-disintegrating agents or encapsulating materials. In powders, the carrier may be a finely divided solid which is in admixture with a finely divided compound of formula I. In tablets, the formula I compound may be mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired. Said powders and tablets may contain up to 99% by weight of the formula I compound. Solid carriers suitable for use in the composition of the invention include calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins.
Any pharmaceutically acceptable liquid carrier suitable for preparing solutions, suspensions, emulsions, syrups and elixirs may be employed in the composition of the invention. Compounds of formula I may be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, or a pharmaceutically acceptable oil or fat, or a mixture thereof. Said liquid composition may contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, coloring agents, viscosity regulators, stabilizers, osmo-regulators, or the like. Examples of liquid carriers suitable for oral and parenteral administration include water (particularly containing additives as above, e.g., cellulose derivatives, preferably sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, e.g., glycols) or their derivatives, or oils (e.g., fractionated coconut oil and arachis oil). For parenteral administration the carrier may also be an oily ester such as ethyl oleate or isopropyl myristate.
Compositions of the invention which are sterile solutions or suspensions are suitable for intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions may also be administered intravenously. Inventive compositions suitable for oral administration may be in either liquid or solid composition form.
For a more clear understanding, and in order to illustrate the invention more clearly, specific examples thereof are set forth hereinbelow. The following examples are merely illustrative and are not to be understood as limiting the scope and underlying principles of the invention in any way.
The term NMR designates proton nuclear magnetic resonance. The terms THF and EtOAc designate tetrahydrofuran and ethyl acetate, respectively.